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Mir-340-FHL2 Axis Inhibits Cell Growth and Metastasis in Ovarian

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Mir-340-FHL2 Axis Inhibits Cell Growth and Metastasis in Ovarian Huang et al. Cell Death and Disease (2019) 10:372 https://doi.org/10.1038/s41419-019-1604-3 Cell Death & Disease ARTICLE Open Access miR-340-FHL2 axis inhibits cell growth and metastasis in ovarian cancer Zheng Huang1,QiuxiaLi1, Kaili Luo1, Qinkai Zhang1,JingwenGeng1, Xunzhu Zhou1, Yesha Xu1,MengyaoQian1, Jian-an Zhang2, Liying Ji1 and Jianmin Wu1 Abstract Although increasing evidence indicated that deregulation of microRNAs (miRNAs) contributed to tumor initiation and progression, but little is known about the biological role of miR-340 in ovarian cancer (OC). In this study, we found that miR-340 expression was downregulated in OC tissues compared with its expression in normal ovarian epithelium and endometrium, and treatment with 5-aza-2′-deoxycytidine (5-Aza-dC) or trichostatin A (TSA) increased miR-340 expression in OC cells. In addition, ectopic miR-340 expression inhibited OC cell growth and metastasis in vitro and in vivo. Four and a half LIM domains protein 2 (FHL2) was confirmed as a direct target of miR-340 and silencing FHL2 mimicked the effects of miR-340 in OC cells. Further mechanistic study showed that miR-340 inhibited the Wnt/ β-catenin pathway by targeting FHL2, as well as downstream cell cycle and epithelial-to-mesenchymal transition (EMT) signals in OC cells. Moreover, the greatest association between miR-340 and FHL2 was found in 481 ovarian serous cystadenocarcinoma tissues via pan-cancer analysis. Finally, we revealed that lower miR-340 or higher FHL2 was associated with poor OC patient outcomes. Our findings indicate that the miR-340-FHL2 axis regulates Wnt/β-catenin signaling and is involved in tumorigenesis in OC. Therefore, manipulating the expression of miR-340 or its target genes is a potential strategy in OC therapy. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; – Introduction leads to a poor 5-year survival rate5 7. Thus, increased Human ovarian cancer (OC) is the leading cause of understanding of the mechanisms driving OC and iden- – death from gynecologic malignancies1 3. Worldwide, tification of new therapeutic targets are needed to ~295,400 new cases of OC have been diagnosed and improve OC treatments. 184,800 women are expected to succumb to the disease in Wingless/integrated (Wnt)-mediated signal transduc- 20184. This case-to-fatality ratio is nearly twice that of tion pathways are known to regulate development and – breast cancer4. Due to high tumor heterogeneity and lack stemness, but are also tightly associated with cancer8 10. of reliable detection markers, the majority of OC patients Activated Wnt signaling has been reported to mediate OC are diagnosed at advanced stages. Despite high response initiation and progression by regulating cell proliferation rates for initial chemotherapy, many patients develop and apoptosis, even epithelial-to-mesenchymal transition recurrent disease with chemoresistance which ultimately (EMT)11,12. The Wnt signaling pathway is commonly divided into β-catenin-dependent (canonical) and β-catenin-independent (noncanonical) signaling8,9. The Correspondence: Jianmin Wu ([email protected])([email protected]. canonical pathway is activated upon Wnt ligand binding cn) to Frizzled receptors and LDL-receptor-related protein 1Institute of Genomic Medicine, Wenzhou Medical University, 325000 Wenzhou, Zhejiang, P. R. China (LRP) co-receptors. These interactions disrupt the ade- 2Department of Obstetrics and Gynecology, The Second Affiliated Hospital and nomatous polyposis coli (APC)/Axin/casein kinase 1 Yuying Children of Wenzhou Medical University, 325027 Wenzhou, Zhejiang, alpha (CK1A)/glycogen synthase kinase 3 beta (GSK3β) P. R. China These authors contributed equally: Zheng Huang, Qiuxia Li, Kaili Luo complex, which results in the translocation and Edited by A. Peschiaroli © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Huang et al. Cell Death and Disease (2019) 10:372 Page 2 of 16 accumulation of β-catenin in the nucleus, where it acti- (DMEM, BI, Israel). HEK293T and SKOV3 cells were vates target gene expression by interacting with T-cell grown in Roswell Park Memorial Institute (RPMI) 1640 factor/lymphoid enhancer-binding factor (TCF/LEF) medium (BI). All media were supplemented with 10% fetal transcription factors8,9. bovine serum and the cells were incubated at 37 °C in a Four and a half LIM domains protein 2 (FHL2) is a humidified incubator with 5% CO2. Cell line authentica- multifunctional scaffolding protein regulating signaling tion was achieved by genetic profiling using polymorphic cascades and gene transcription13. FHL2 has been impli- short tandem repeat loci. The cells were treated with 5- cated in the Wnt/β-catenin signaling pathway14. FHL2 aza-2′-deoxycytidine (5-Aza-dC) or trichostatin A (TSA) was first reported as a coactivator of β-catenin15 that at the indicated concentrations for 48 or 24 h, respec- promoted differentiation of mouse myoblasts16.In tively, before subsequent analysis. osteosarcoma and colon cancer, FHL2 can stabilize nuclear β-catenin, resulting in enhanced β-catenin Microarray data analysis transactivation activity17,18. FHL2 was also shown to Microarray datasets were obtained from Gene Expres- promote tubular EMT through modulation of β-catenin sion Omnibus (GEO): GSE71477 (eight groups including signaling in fibrotic kidneys19. Consistent with aberrant 19 paired tissue samples representing OC and endome- Wnt/β-catenin signaling, the expression of FHL2 was trium) and GEO: GSE47841 (including 9 ovarian surface dysregulated in several types of cancers, including epithelium scraping samples and 12 high-grade serous – OC18,20 22. Recently, FHL2 has been shown to regulate ovarian carcinoma samples). miRNAs upregulated by ovarian granulosa cell tumor progression via controlling >1.25-fold or downregulated by <0.8-fold (P < 0.025) in AKT1 transcription23. Nevertheless, the precise molecular the OC samples were considered to be dysregulated. The mechanism of FHL2’s involvement in OC remains far heat-map was plotted using MEV 4.9.0 software. from being understood. MicroRNAs (miRNAs) are non-coding RNAs ~22 Establishment of stable OC cell lines nucleotides in length that can influence a wide range of To generate stable miR-340-overexpressing cells, A2780 biological processes by repressing target mRNA levels24,25. and SKOV3 cells were transduced with a lentivirus Increasing evidence has demonstrated that miRNAs are expressing miR-340 or a negative control (Genechem, highly dysregulated in cancers, suggesting that they can Shanghai, China), according to the manufacturer’s – function as therapeutic targets in tumorigenesis24 26. instructions, and selected using 500 ng/mL puromycin. MicroRNA-340 (miR-340) has been identified as one of After 6 days, puromycin-resistant cell pools with green the miRNAs that are downregulated in several types of fluorescent protein signals were identified using laser cancer. miR-340 can inhibit cell proliferation, induce cell scanning confocal microscopy, collected, and then verified apoptosis, and reduce cell migration and invasion by tar- by real-time RT-PCR. To generate stable miR-340 and geting multiple oncogenes in breast cancer, gastric cancer, FHL2 co-expressing cells, the lentiviral particles were first – glioblastoma, and non-small cell lung cancer27 32. produced in HEK293T cells co-transfected with p-FHL2 Accordingly, some signaling pathways related to tumor- plasmid (EX-M0686-Lv105-5, Genecopoeia, USA) or igenesis, such as Janus kinase/signal transducers and control plasmid (EX-eGFP-Lv105, Genecopoeia) along activators of transcription (JAK/STAT), Wnt/β-catenin, with psPAX2 (Addgene, Watertown, MA, USA) and and RAS/RAF/mitogen-activated protein kinase (MAPK), pMD2.G (Addgene) plasmids. Lv-miR-340-SKOV3 cells – were shown to be suppressed by miR-34033 35. were then transduced with the resulting lentiviral particles The purpose of the present study was to investigate the and selected using 1000 ng/mL puromycin. After 6 days, molecular function of miR-340, as well as its regulatory puromycin-resistant cell pools were collected and verified mechanisms in OC. We found that downregulation of miR- by western blotting. 340 in OC was due to the promoter hypermethylation, which is associated with poor patient outcomes. miR-340 siRNA and transfection inhibited cell growth, promoted apoptosis, and reduced siRNAs targeting FHL2 were obtained from Gene- migratory and invasive ability in vitro and in vivo by directly Pharma (Shanghai, China). siRNA was transfected at a targeting FHL2. Moreover, we identified that the miR-340- final concentration of 50 nM using Lipofectamine 2000 FHL2 axis regulated Wnt/β-catenin signaling in OC cells. (Life
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